INTRAUTERINE GROWTH RESTRICTION

Intrauterine growth retardation (IUGR
? also known as intrauterine growth restriction or small for gestational age
- SGA) occurs when the fetus is less than 10 percent of predicted fetal
weight for gestational age. It can result in significant fetal morbidity and
mortality1998-01 if not properly diagnosed and managed.
The reason that studies on SGA fetuses have shown poor perinatal outcome is
likely to be the high incidence of true Fetal Growth Retardation in this
group.1998-02 The condition is most
commonly caused by inadequate maternal-fetal circulation. Less common causes
include intrauterine infections such as cytomegalovirus and rubella, and
congenital anomalies such as trisomy 21 and trisomy 18. When IUGR is
recognized, it is important to attempt to correct reversible causes,
although many of the conditions responsible for IUGR are not correctable.
Close fetal surveillance with delivery before 38 weeks of gestation is
usually recommended. Some infants born with IUGR have reduced mental ability
and medical problems, although for most infants the long-term prognosis is
good.However, the vast majority of term SGA infants have no
appreciable morbidity or mortality.1986-01

At one time, all babies born
weighing less than 2,500 g (5 lb 8oz) were classified as ?premature?. In
1961 the World Health Organization (WHO) acknowledged that many infants
defined as "premature" were not born early but were simply of "low birth
weight." The current WHO criterion for low birth weight is a weight less
than 2,500 g (5 lb, 8 oz) or below the 10th percentile for gestational age.

Low birth weight includes two
pathologic conditions and one normal condition. The normal condition refers
to the healthy but constitutionally small baby. The pathologic conditions
include preterm delivery and intrauterine growth retardation (IUGR).
Synonymous terms found in the literature to describe infants with IUGR
include intrauterine growth restriction and fetal growth retardation. IUGR
is linked to an increase of six to 10 times in perinatal mortality.

Epidemiology of

According to the common definition
of IUGR as a birth weight under the 10th percentile, the expected incidence
of IUGR should be 10 percent. The actual incidence, however, is only about 6
percent. About a quarter of infants who are below the 10th percentile have a
normalized birth weight when it is corrected for low maternal weight,
paternal phenotype or residence at higher altitudes.1992-01

The approximately 3.5 million
annual births in the United States result in 350,000 infants who are born
weighing less than 2,500 g (5 lb, 8 oz). Approximately one third of these
infants (about 100,000) have true IUGR, and the remaining two thirds (about
250,000) are constitutionally small.

Etiology

Many different factors cause IUGR,
but they may be divided into two large categories, based on etiology. These
categories include fetoplacental factors and maternal factors. Within the
categories of maternal and fetoplacental factors are many specific causes.

Historically, IUGR has been
categorized as symmetric or asymmetric. Symmetric IUGR refers to fetuses
with equally poor growth velocity of the head, the abdomen and the long
bones. Asymmetric IUGR refers to infants whose head and long bones are
spared compared with their abdomen and viscera. It is now believed that most
IUGR is a continuum from asymmetry (early stages) to symmetry (late stages).

Maternal causes of IUGR account for
most uteroplacental cases. Chronic hypertension is the most common cause of
IUGR. Moreover, the infants of hypertensive mothers have a three-fold
increase in perinatal mortality compared with infants with IUGR who are born
of normotensive mothers.

Pre-eclampsia causes placental
damage that result in uteroplacental insufficiency. The pathogenic mechanism
is thought to be a failure of trophoblastic invasion by maternal spiral
arterioles by 20 to 22 weeks of gestation. This failure causes luminal
narrowing and medial degeneration, leading to diminished blood flow to the
developing infant. Consequently, these infants fail to grow normally.

Infectious causes of fetal growth
delay account for about 10 percent of all cases of IUGR. These causes
include the "TORCH" group: Toxoplasma, rubella, cytomegalovirus and herpes
simplex virus types 1 and 2. Other potential pathogens include hepatitis A
and hepatitis B, parvovirus B19, human immunodeficiency virus (HIV) and
Treponema pallidum (syphilis). Maternal pre-pregnancy weight and weight gain
during pregnancy are considered strong indicators of birth weight. The
current consensus is that a maternal weight gain of less than 10 kg (22 lb)
by 40 weeks of gestation is clearly a risk factor for IUGR.

Early use of alcohol by the
pregnant mother may lead to fetal alcohol syndrome, while second- or
third-trimester use may result in IUGR. As little as one to two drinks per
day have been shown to result in a growth-delayed child.1984-01
Maternal cocaine use has been linked to IUGR, as well as to reduced head
circumference.2002-01
Other drugs associated with IUGR include steroids, warfarin and phenytoin.

Intrauterine growth retardation
occurs more frequently in twin deliveries than in single gestations.2005-01
Decreased birth weight is second only to respiratory distress syndrome as a
cause of infant mortality in twins. Reasons for IUGR in twin pregnancies
include poor placental implantation, placental crowding and twin-to-twin
transfusion.

Diagnosis

Methods employed to detect SGA fetuses include abdominal palpation,
measurement of symphyseal fundal height, ultrasound biometry, ultrasound
estimated fetal weight and ultrasound Doppler flow velocimetry. Four
important issues need to be considered with the use of these tests:

most measurements require an accurate estimation of gestation as a
prerequisite
most tests attempt to diagnose SGA fetuses rather than growth-restricted
fetuses
most studies use a one-off measurement (size) to predict SGA while there
is evidence that it is the trend (growth) that is of more value in
predicting poor fetal outcome.1993-01,
1994-01
in most situations no allowance is made for important prognostic factors
for SGA, such as maternal height, weight, ethnicity, parity and fetal
gender.1995-01,
1998-03

The main prerequisite for
determining IUGR is precise dating. The most accurate dating method uses
ultrasound examination at eight to 13 weeks. Later ultrasound examinations
are helpful, but the margin of error is increased. The date of the last
menstrual period, early uterine sizing and detection of fetal heart tones
are helpful ways to accurately date the pregnancy. Most cases of IUGR
present during the third trimester, which makes them difficult to accurately
diagnose. This is especially true if the patient has presented for prenatal
care at a late stage. The physician must determine if the dating is
incorrect and the fetal size is actually normal or if the mother truly needs
further evaluation for IUGR.

Before the development of
ultrasonography, indicators of possible delayed fetal growth were low
maternal weight gain and fundal height measurement.

Physical examination of the abdomen by inspection and palpation detects as
few as 30% SGA fetuses.1982-01
Therefore, if SGA is suspected, it is necessary to supplement abdominal
palpation with ultrasound biometric tests.

Currently, IUGR is still
often suspected on the basis of fundal height measurements. A significant
lag in fundal height is a 4-cm or greater difference than expected for
gestational age.Although early studies reported sensitivities of
56?86%26?29 and specificities of 80?93%1985-02,
1987-02,
1986-02 for
fundal height to predict SGA neonates, a large study1986-03
of 2941 women found the sensitivity and specificity to be 27% and 88%,
respectively. Serial measurements may improve sensitivity and specificity.1987-03
The impact on perinatal outcomes of measuring fundal height is uncertain. A
systematic review found only one controlled trial with 1639 patients and
showed that SFH measurement did not improve any of the perinatal outcomes
measured.2000-01
Low sensitivity, high false positive rates, significant intra- and
inter-observer variation1989-03
make this test alone unsuitable for diagnosis. Therefore, if SGA is
suspected, it is necessary to supplement fundal height measurement with
ultrasound biometric tests.

A customised SFH chart is adjusted for physiological variables such as
maternal height, weight, parity and ethnic group. Use of such charts was
found to result in improvement in sensitivity (29% and 48% using
non-customised and customised charts, respectively), resulting in increased
antenatal detection of SGA babies with a
reduction in unnecessary hospital investigations for fetal growth.1999-01
Calculation of customised centiles (both for fundal height and ultrasound
growth) requires computer software that can be downloaded from the Internet
(www.gestation.net), free of charge,
for personal or institutional use. These charts can then be printed and
incorporated into patient-held records at the time of booking.

IUGR is frequently detected in a pregnancy with a
less-than-expected third-trimester weight gain or as an incidental finding
on ultrasound examination when fetal measurements are smaller than expected
for gestational age.

When the suspicion of IUGR is
strong, a complete assessment of maternal risk factors should be undertaken.
This includes past medical and obstetric history, medication use, recent
infections, occupational or toxic exposures, and a history of tobacco,
alcohol or illicit drug use.

Ultrasonography is normally the
first study done to assess IUGR. This test loses its accuracy as the
pregnancy progresses, but the sensitivity and positive predictive value can
be improved if several variables are combinedincluding estimated
fetal weight, head circumference and abdominal circumference.

Estimated fetal weight is the most
common screen. It is based on the measurements of head circumference,
abdominal circumference and femur length. These measurements are plotted on
a preexisting standardized chart. In about 95 percent of cases, ultrasound
examination allows an estimation of fetal weight with a 15 to 18 percent
variance. An estimated fetal weight of less than the sixth percentile
strongly correlates with growth retardation, and an estimated fetal weight
of greater than the 20th percentile virtually rules out IUGR.

In all growth-retarded fetuses, the
abdominal circumference is the first biometric measure to change. The ratio
of head circumference to abdominal circumference is normally one at 32 to 34
weeks and falls below one after 34 weeks. A ratio of greater than one
detects about 85 percent of growth-restricted fetuses.

Serial measurements of AC and EFW (growth velocities) are superior to single
estimates of AC or EFW in the prediction of FGR (abnormal neonatal ponderal
index and skinfold thickness)18 and predicting poor perinatal outcome.1994-01,
1999-02However, use of fetal growth alone to diagnose growth restriction
(especially when the interval
between the scan is less than two weeks) can lead to high numbers of false
positives.1998-04
The first radiographic sign of IUGR
may be decreased amniotic fluid volume. About 85 percent of IUGR infants
have oligohydramnios. This condition occurs because blood flow from
peripheral organs (kidneys) is diverted to the brain. Renal perfusion and
urinary flow rates are commonly reduced in infants with IUGR.1989-01
An amniotic fluid index of less than 5 cm increases the risk of IUGR. A
vertical pocket of amniotic fluid less than 1 cm, regardless of gestational
age, is found in about 39 percent of cases of IUGR. A systematic
review in the Cochrane Database of Systematic Reviews has shown that routine
ultrasound after 24 weeks in low-risk pregnancy does not improve perinatal
poutcome.2007-01

Maternal arterial umbilical blood
flow increases from 50 mL per minute early in pregnancy to about 700 mL per
minute at term. The increase is secondary to a gradual decrease in vessel
resistance to blood flow throughout the pregnancy. Doppler velocimetry uses
ultrasound to measure peak-systolic and end-diastolic blood flow through the
umbilical artery. Three measurements are averaged as the systolic/ diastolic
ratio. As the pregnancy progresses, diastolic flow increases, and the
systolic/diastolic ratio should gradually decrease. In a large number of
IUGR pregnancies, an alteration in placental blood flow occurs. As a result,
researchers have correlated an increased systolic/diastolic ratio with IUGR.
The ratio is increased in about 80 percent of cases of IUGR diagnosed by
ultrasound examination.1989-02
An average systolic/ diastolic ratio greater than three at 30 or more weeks
of gestation has a sensitivity of 78 percent and a specificity of 85 percent
in predicting IUGR.1985-01
A systematic review with meta-analysis2000-02
found that uterine artery Doppler had limited accuracy in predicting FGR and
perinatal death. In the low-risk population the pooled LR to predict FGR was
3.6 for a positive test and 0.8 for a negative test. Even in the high-risk
population the pooled LRs were 2.7 and 0.7 for positive and negative tests,
respectively.

Ultrasonographic placental grading
has been studied with respect to IUGR. Normally, a grade 3, or mature,
placenta would not be detected before 36 weeks of gestation. The presence of
a grade 3 placenta before 36 weeks, along with an estimated fetal weight of
less than 2,700 g (5 lb, 14 oz), carries a four-fold risk of IUGR.1983-01

A distinction needs to be made between biometric tests (tests to measure
size) and biophysical tests (tests to assess fetal wellbeing). Biometric
tests are designed to predict size and, if performed longitudinally, growth,
but not wellbeing. Biophysical tests, on the other hand, are not designed to
predict size but fetal wellbeing. The presence of fetal wellbeing implies
the absence of fetal acidaemia. This distinction implies that the diagnosis
of SGA would rely on biometric tests while abnormal
biophysical tests are more indicative of FGR than SGA.

Antenatal
Surveillance

When the diagnosis of IUGR has been
established, it is helpful to determine a specific etiology. Therapy may be
nonspecific but should try to address the underlying cause. Many infants
thought to be growth-retarded are, in retrospect, found to be
constitutionally small. The key management issues are the gestational age of
the pregnancy at the time of diagnosis and the urgency to expedite delivery.
Most fetal deaths involving IUGR occur after 36 weeks of gestation and
before labour begins. The clinician must balance the risk of delivering a
premature infant against the potential for intrauterine demise.

Ultrasonography at three- to
four-week intervals is recommended to assess fetal growth. Third-trimester
fetal weight gain should be 100 to 200 g per week. Head circumference that
does not change over a four-week period is worrisome and may be an
indication for prompt delivery.

Twice-weekly non-stress testing (NST)
is an appropriate surveillance method in following a fetus with IUGR. A
reactive NST (two accelerations in fetal heart rate of more than 15 beats
per minute lasting for more than 15 seconds in a 20-minute span) has been
shown to correlate with fetal well-being. Spontaneous variable decelerations
in fetal heart rate on the NST may indicate oligohydramnios and an increased
risk of perinatal mortality. A nonreactive The biophysical profile includes
an NST, fetal breathing movements, gross body movements, fetal tone and
amniotic fluid index. Two large studies1987-01
found the biophysical profile to be predictive of fetal well-being, fetal
distress and ultimate perinatal mortality.

Doppler velocimetry, previously
discussed as a diagnostic technique for IUGR, has not found a place in
routine antenatal surveillance. It has helped physicians understand the
pathophysiology of IUGR with regard to diminished blood flow. Results of
this procedure correlate with increased fetal morbidity and mortality: an
absent or reversed end-diastolic umbilical flow is an ominous finding and
necessitates aggressive intervention. As a screening test, however, the
procedure appears to be lacking in benefit; some studies have shown that 40
to 60 percent of infants with IUGR had normal Doppler velocimetry results
just before birth.

The biophysical profile has not been shown to improve perinatal outcome but
sufficient data do not exist to rule out its value: a systematic review2000-05
found only four poor-quality studies with fewer than 3000 patients. Authors
of the systematic review concede that to make a meaningful conclusion about
the impact of biophysical profile on perinatal mortality, in excess of 10
000 women would need to be studied. However, there is evidence from
uncontrolled observational studies that biophysical profile in high-risk
women has good negative predictive value, i.e. fetal death is rare in
women with a normal biophysical profile.1993-03
Given the absence of benefit from randomised trials and that biophysical
profile is a time-consuming test, it cannot be recommended for routine
monitoring in lowrisk/ unselected pregnancies or for primary surveillance in
SGA fetuses. However, when primary surveillance with umbilical artery
Doppler is found to be abnormal, biophysical profile is likely to be useful
given its good negative predictive value in high-risk populations.

Use of cardiotocography (CTG) antepartum to assess fetal condition is not
associated with better perinatal outcome; in fact, a systematic review of
randomised trials showed that there was a trend towards increased mortality
in the group receiving CTG compared with those who did not.2000-06
Computer systems for interpretation of CTG have better accuracy than
clinical experts in predicting umbilical acidosis and depressed Apgar
scores.1988-02
However, further evaluation of this technology is required before clinical
recommendations could be made regarding its widespread use.

Treatment

Treatment of the mother and the
growth-restricted fetus is, when possible, dictated by the aetiology of the
condition.Up to 19% of fetuses with an AC and EFW less than the
fifth centile may have chromosomal defects.60 The risk is higher when growth
restriction is associated with structural abnormalities,60 a normal
liquor volume or a normal uterine or umbilical artery Doppler.1993-02
Therefore, all growth-restricted fetuses need an ultrasound anatomical
survey as a minimum. It may also be appropriate to offer karyotyping.

A systematic review with meta-analysis has provided compelling evidence that
the use of umbilical artery Doppler to monitor high-risk fetuses reduces
perinatal morbidity and mortality.1995-02
Furthermore, there was a significant reduction in the number of antenatal
admissions and inductions of labour. Use of Doppler does not lead to
increased interventions as the rates of positive test are low (2.7% of all
umbilical artery tests in high-risk women).1990-01
There is evidence that use of Doppler ultrasound to manage SGA fetuses
reduces the use of resources compared with cardiotocography.1997-01

When an anomaly scan and umbilical artery Doppler are normal, the small
fetus is likely to be a ?normal small fetus?.1993-03
Evidence suggests that outpatient management of such fetuses is safe.1997-02
In addition, a randomised controlled trial2003-01
of two regimens of fetal surveillance for SGA fetuses with normal umbilical
artery Doppler found that twice-weekly compared with fortnightly monitoring
resulted in earlier deliveries and more inductions of labour with no
difference in neonatal morbidity. This suggests frequency of monitoring in
SGA fetuses with normal Doppler need not generally be more than once every
fortnight.

Abnormal liquor volume has been variously defined as single cord-free
1-cm, 2-cm, 1-x-1-cm, 2-x-1- cm and 2-x-2-cm pockets or an AFI below the
fifth centile for the gestation or ≤ 5 cm.2004-04
Other large studies1984-02,1986-04
have shown that a reduction in liquor volume is associated with increased
perinatal mortality compared with controls with normal liquor volume.

Management

Maternal hyperoxygenation has been
evaluated in several studies, but only limited data prove its efficacy. In
one study,1991-01
nasal oxygen at 2.5 L per minute administered to mothers at 27 to 28 weeks
of gestation improved neonatal blood gas measurements but resulted in an
increased incidence of hypoglycemia and thrombocytopenia in the infants.

Low-dose aspirin (150 mg per day)
as a treatment for IUGR has been studied over the past several years. One
study1998-011991-02
aspirin, given in a dosage of 150 mg per day with dipyridamole in a dosage
of 225 mg per day and administered at 15 to 18 weeks of gestation in
high-risk patients, resulted in a lower incidence of still-birth, placental
abruption and IUGR. Birth weight was improved, and no excess of maternal or
fetal aspirin-related side effects occurred. It would seem prudent to
consider low-dose aspirin therapy in selected patients with risk factors for
IUGR.

Approximately one half of infants
with IUGR have intrapartum asphyxia and lower Apgar scores than control
subjects. A higher incidence of meconium aspiration has also been noted in
these infants. Continuous monitoring of fetal heart rate throughout labour
is , therefore, recommended in cases of IUGR. Late decelerations are more
predictive of fetal hypoxia and a resultant adverse outcome in this group of
high-risk infants. A lower threshold for the choice of caesarean section is
therefore recommended. Neonatal resuscitation and subsequent care of the
growth-restricted infant should follow in the same manner used with other
newborns. Problems to closely watch out for in infants with IUGR include
hypoglycemia, hypocalcemia, polycythemia secondary to intrauterine hypoxia
and hypothermia due to decreased body fat.

There is wide variation in practice in the timing of delivery of growth
restricted fetuses.1996-02
But thus far there is no evidence from GRIT that early delivery to pre-empt
severe hypoxia and acidosis reduces any adverse outcome.2004-01

Absent or reversed end diastolic flow is associated with increased perinatal
mortality and morbidity.1994-03,1994-041996-03

When end
diastolic flow is absent or reversed, admission, close surveillance and
administration of steroids are required. If other surveillance results
(biophysical profile, venous Doppler) are abnormal, delivery is indicated.
If gestation is over 34 weeks, even if other results are normal, delivery
may be considered.

Most prenatal interventions do not show any significant effects on perinatal
outcome. Smoking cessation programmes, particularly behavioural strategies,
can be effective for a small minority of smokers in increasing birthweight
but there are no data to suggest that this intervention improves perinatal
outcome.2001-01
Although a meta-analysis102 of 13 trials evaluated the use of aspirin in the
prevention of growth restriction and found that it reduced the incidence of
FGR, only a few studies have used aspirin in the treatment of FGR. These
trials are small and have shown conflicting results.1999-04,1995-03 Further trials are needed to assess the value of aspirin
in the treatment of FGR. There is not enough evidence to assess the
value of oxygen therapy,2003-01
hospitalisation and bedrest,2000-07
betamimetics,2001-02 hormonal therapy2003-02
and plasma volume expansion2000-08 in treating growth restriction.

Neonatal
Outcomes

In most cases, infants with IUGR
ultimately have good outcomes. These infants often exhibit fast catch-up
growth in the first three months of life and attain normal growth curves by
one year of age. Some studies have found a variety of long-term
complications in infants with IUGR including hyperactivity, clumsiness and
poor concentration.

In a recent British study,1996-01
records of 1,576 men and women born between 1920 and 1943 for whom birth
weight and anthropomorphic measurements were recorded in detail after birth
were examined. No definite association was found between cognitive function
(intelligence quotient and vocabulary) and birth weight, head circumference
or ratio of head circumference to abdominal circumference. Collectively,
developmental studies demonstrate that many factors contribute to the
ultimate intellectual development of infants with IUGR, including birth
weight, time of onset of IUGR, head circumference, gestational age at
delivery, etiology of the IUGR and postnatal environment. Most infants with
IUGR have an excellent long-term prognosis.

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